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The biochemical pathway of ATP by red blood cells elucidated

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The understanding of the mechanisms of biochemical signaling, which is ubiquitous in the vascular network, is essential for the design of therapies adapted to cardiovascular pathologies. The release of ATP (Adenosine Triphosphate) by red blood cells is a major mechanism that has been modeled in this work, in agreement with experiments conducted at Harvard.

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The vascular network is a fascinating biochemical signaling system, in which different types of cells participate, such as red blood cells, white blood cells, and endothelial cells (which line the inner sides of blood vessels). An alteration of this signaling is at the origin of multiple dysfunctions leading to pathologies. An understanding of this problem requires a complex modeling and simulation involving blood flow, its interaction with the endothelium and the reactions and transport of the biochemical elements involved. Such modeling has long remained as a major challenge that researchers from the Interdisciplinary Laboratory of Physics (LIPhy, CNRS / Universit√© Grenoble Alpes), in collaboration with the laboratory waves and matter of Aquitaine (LOMA, CNRS / Bordeaux University) and the Laboratory of hydrodynamics of the Polytechnic School (LadHyX, CNRS / X) have just defied. To illustrate their work, the researchers took as an example the release of ATP - the body’s major source of energy - from red blood cells.
Red blood cells are commonly known as oxygen cargo. In reality, they also carry ATP. For example, in case of lack of oxygen, ATP is released by red blood cells to cause vasodilatation and thus increase blood flux. A fall in ATP release from red blood cells is associated with conditions such as type II diabetes and cystic fibrosis (a genetic disorder that mainly affects the lungs and the digestive system). The release of ATP by red blood cells is a process involving a change of conformation of membrane proteins and the modeling of the mechanisms involved has long been a big challenge for scientists.

In this work, researchers have proposed a release model that involves two mechanisms. The first consists in the existence of a threshold in hydrodynamic stresses due to the blood flow felt by the red blood cells, which induces a conformational change of a membrane protein allowing the local release of ATP. The second mechanism is related to the deformation of red blood cells. If the membrane curvature of these exceeds a critical value, defects are created in the underlying actin network, which aggregate on another protein which in turn stimulates the release of ATP. By proposing this model and solving it numerically by the "Lattice Boltzmann" method, a good agreement is obtained between the model and results from recent in vitro experiments carried out at Harvard University (Fig.1). In addition, this study highlights the important role played by the bifurcations of the vascular network which strongly enhance the release of ATP (Fig. 2).

This work opens many perspectives for systematic simulation involving blood flow and biochemical signaling in vascular networks. It should help to understand how biochemical signaling is involved in cardiovascular pathologies. For example, this may elucidate the question of how the distribution of ATP is impaired in vascular networks of patients with diabetes, and thereby better guide research for the development of appropriate therapies.

View online : ATP Release by Red Blood Cells Under Flow: Model and Simulations Hengdi Zhang, Zaiyi Shen, Brenna Hogan, Abdul I. Barakat et Chaouqi Misbah Biophysical Journal (2018)